Managing recurrent thymic epithelial tumors after resection: outcomes and role of re-resection

Introduction

Thymic epithelial tumors (TETs) are rare neoplasms, with an incidence of 0.15 per 100,000 person-years (1), although they are the most common tumors arising from the anterior mediastinum. Although both the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines suggested that recurrent TETs should be managed following the same strategy as newly diagnosed tumors (2,3), due to the low incidence of the disease, and limited knowledge of its biology, the establishment of standard treatment based on prospective studies has not yet been achieved. Treatments, including surgery, have been recommended for resectable cases, and induction therapies are considered for locally advanced cases. In selected cases of thymomas that initially appear with pleural disease, surgical resection has been indicated to achieve complete macroscopic resection due to their indolent characteristics.

Despite efforts by physicians, not a small proportion, 10–40% of patients with TET experience recurrence, those are 13.9–22.3% in all TETs (4-6), 36.6–87.0% in thymomas (7-11), 39.4% in thymic cancers (TCs) and thymic neuroendocrine neoplasms (TNENs) (12) (Table 1), and treatment is required after complete resection. In cases of recurrence of other malignant neoplasms, surgical resection has been indicated for limited and/or pleural disease based on previous studies, which mainly consisted of retrospective cohort studies, including a small series.

In this literature, we review previous literature regarding the treatment of recurrent TETs, including thymomas, TCs, and TNENs, and aim to provide a perspective on current treatment strategies, especially those focusing on surgical resections. We searched articles published after 2010 using the terms recurrence, thymic tumor, and resection in the PubMed database. Articles including 20 or more treated patients with recurrence were selected for discussing re-resection for TETs.

Initial treatment course of TETs and afterward

The current World Health Organization (WHO) classification divides this entity into thymomas, TCs, and TNENs (16). They have a wide range of histological characteristics and malignant potentials. Surgical resection is considered the mainstay of treatment for these tumors if they are resectable. Preoperative treatment is considered for complete resection during surgery for locally advanced diseases with invasion of neighboring structures, including the great vessels. After complete resection is achieved, the disease control and prognosis of patients are usually favorable. However, a significant proportion of patients experience disease recurrence, which sometimes develops at a later stage and is subsequently diagnosed late. A mean recurrence-free interval (RFI) of more than 5 years after initial resection was documented (7,13,14) (Table 2). The WHO histological type, tumor size at initial treatment, pathological stage, and completeness of initial resection have been suggested as potential risk factors for recurrence after resection. There are various disease statuses at the time of recurrence diagnosis. Treatment strategies are planned based on factors including extent of disease, disease-free interval (DFI), WHO histological type, patient symptoms, and presence of comorbidities, including autoimmune myasthenia gravis (MG).

Incidence and mode of recurrence of TETs after initial resection

Owing to their indolent biological nature, disease control of thymomas is comparatively favorable after initial resection. Recurrence rates have been reported to be 10.3–15.1% in resected thymoma cases (7-11) (Table 1). According to the Japanese Association of Research for Thymus (JART), the recurrence rate after resection was 10.0% (6). Differential recurrence rates were reported according to the WHO Health Organization histologic type and initial stage. According to a report by Bae et al., the recurrence rates of types A, AB, B1, B2, and B3 were 0, 6.3, 4.2, 18.2, and 20.7%, respectively, indicating high recurrence rates of Type B2–3 thymoma. Regarding the initial stage, Masaoka stages I, II, III, and IV recurrence rates were 6.0%, 11.4%, 26.8%, and 50%, respectively, and higher recurrence rates were identified in advanced stages (9).

The modes of recurrence of resected thymomas are distinctive compared to those of other malignancies, including TCs and TNENs. Sandri et al. reported that 58% of the pleural/pericardium sites and 18.5% of the mediastinum were recurrent sites in thymomas (13). Chiappetta et al. documented 12.5% of local sites, 71.8% of regional sites, including the pleura, and 15.7% of distant sites, following the definition proposed by the International Thymic Malignancy Interest Group (ITMIG) (15). This proposal defines local recurrence as a disease in the anterior mediastinum or tissues contiguous with the resected primary thymoma, regional recurrence as intrathoracic recurrence, and distant recurrence as extrathoracic recurrence and intraparenchymal pulmonary nodules (17). Considering the trends in recurrence sites with a low incidence of distant recurrence, we have acknowledged that we often indicate local therapies such as surgery and/or radiotherapy to treat recurrent thymoma after resection.

Higher recurrence rates have been observed in patients with resected TCs. Ruffini et al. documented 28% (18), Hamaji et al. did as high as 40.9% (5), and Hishida et al. did 39.1% of recurrent rate after R0 resection (19). In these reports on TCs, the incidence and the modes of recurrence were different from those of thymomas. Many patients experience recurrence at distant sites in the lungs, bone, brain, and liver, and local therapies are unfavorable (5,20).

In recurrent thymoma cases, the proportion of patients indicated for re-resection ranged from 36.6% to 87.0% (7-11,13-15) (Table 1). These differences were assumed to be due to the treatment period, different modes of recurrence by cohort, and the treatment policies of physicians. In the JART cohort, one of the largest series, resections were indicated in 49.8% of recurrent thymoma cases and 24.4% of recurrent TCs cases, showing frequent indications for re-resection in thymoma cases (6). In the combined analyses of recurrent TCs and TNENs, surgery was performed for limited cases, as low as 27% (12).

Prognosis of TETs after recurrence

Most studies have reported the long-term outcomes of 5- and 10-year overall survival (OS) after thymoma recurrence. These values ranged from 52.0–91.0% and 25.1–67.0%, respectively, and included patients treated with re-resection and nonsurgical treatment. In cases of re-resection, the 5- and 10-year OS rates range from 70.5–91.0% and from 58.0–67.3%, respectively (4-15) (Table 2). These are more favorable outcomes than those in non-surgically treated patients, although the survival differences were insignificant in several reports (9,13,14). Better survival of patients with thymomas after recurrence has been documented (5,13). Regarding progression-free survival (PFS) after initial recurrence, for which reports are limited, an identical trend to that in post-recurrent survival (PRS) was observed, and the PFS of TC patients was extremely poor (5).

The effect of recurrence sites on patient outcomes remains controversial. Sandri et al. noted the disease-free survival (DFS) advantages of patients after initial recurrence with local recurrence compared to those with pleural or lung recurrence (13). At the same time, Chiappetta et al. did not show a significant difference in PRS by recurrent sites proposed by ITMIG (15). In cases of pleural recurrence, Choe et al. documented a 5-year OS rate of 73% and a 10-year OS rate of 51% after re-resection in a combined analysis of thymomas and TCs (21). In comparison, Aprile et al. documented 59.9% and 77.0% 10-year-OS rate after re-resection and resection and hyperthermic intrathoracic chemotherapy (HITHOC) in thymoma cases, suggesting the efficacy of HITHOC in combination with surgical resection to prolong the survival of thymoma patients with pleural recurrence (22).

Surgical treatment for recurred disease

For treating recurrent thymic tumors, tumor resection is indicated based on the extent of the disease. The efficacy of perioperative treatments for recurrent disease has not been proven, and their indications have not been fully discussed. They are sometimes used as an initial treatment for locally advanced diseases (9,13-15). The indications may differ among reports; according to Chiappetta et al., perioperative chemotherapy/radiotherapy was indicated in 49% and 57.7% of patients who underwent re-resection (14,15). Conversely, Sandri et al. found that perioperative treatment was indicated for no more than one-fourth of re-resected cases (13).

Furthermore, most studies did not include patient selection for perioperative treatment. The ESMO guidelines recommend cisplatin-based regimens in combination with doxorubicin and cyclophosphamide (CAP) or etoposide (2). CAMP (cisplatin, doxorubicin, cyclophosphamide, methylprednisolone) and ADOC (adriamycin, vincristine, cyclophosphamide, cisplatin) are also being used for advanced cases. In cases of pleural metastases, Choe et al. used CAP regimens in 60% of patients with preoperative treatment, cisplatin and paclitaxel in 13%, and cisplatin and etoposide in 10% (21). After two to four cycles, surgical resection was performed to achieve complete resection, especially for locally recurrent disease. Chemoradiotherapy is sometimes indicated with a better response and subsequent complete resection.

Regarding surgical procedures for pleural disease, partial pleurectomy and pleural decortication are mainly performed, and extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are indicated for selected patients (23). Nakamura et al. reported six cases of pleural recurrence in six thymoma patients treated with multimodality therapy. Two of the six patients underwent EPP, and the remaining four patients underwent pleural resection after CAMP therapy (24). As previously mentioned, the combination of HITHOC with surgery is a treatment option for disseminated diseases of the pleural cavity. Aprile et al. documented better local DFS in patients with HITHOC than in those who underwent surgery alone; however, a significantly favorable OS was not observed (22).

Prognostic factors after re-resection

The PRS has been widely used as a standard outcome measure for factors associated with outcomes after recurrence. In cases of thymoma recurrence, most studies have identified surgical treatment and complete resection as favorable prognostic factors (5-7). Mizuno et al. previously reported that macroscopic complete resection (R0–1) provided a better PRS than macroscopic incomplete resection (R2) and nonsurgical cases from the Japanese database (6). Other studies have suggested that the initial stage, WHO histology, single recurrence, and locoregional recurrence are favorable factors (5,10,13) (Table 2). In DFS analyses, complete resection and the site of recurrence are also potential prognostic factors (13,15). TCs are often evaluated in combination with other types of thymoma. These included limited TCs series, and prognostic factors were not reported (4,5,20).

Role of repeated resection

Thymomas have indolent characteristics and exhibit a less aggressive progression. However, they sometimes develop locally or exhibit pleural recurrence rather than distant metastases. Fiorelli et al. documented 53 cases of thymoma recurrence after complete resection. Among the 38 patients who underwent repeated resection for the first recurrence, 22 (57.9%) experienced a second recurrence. They performed surgery in 3 cases of a fourth recurrence (11). Chiappetta et al. treated 160 patients with thymoma with initial recurrence, and re-resection was indicated in 135 cases (84.3%). A second recurrence developed in 60 cases (37.5%), and multivariable analysis documented that the only independent prognostic factor for OS after the second recurrence was complete surgical resection (14). Their results may indicate that repeated surgeries for recurrence are associated with better survival. These modalities are considered options for thymomas with resectable recurrence. Whether surgical interventions prolong survival has not been proven.

Impact of MG on post-recurrent outcomes

Thymomas are unique neoplasms associated with autoimmune disorders. MG is the most common autoimmune disease accompanied by thymomas, and up to 30% of patients are reported to have the disease. In patients with recurrent disease after thymoma resection, a wide range of patients (13.3–93%) had MG (6,7,11,13,14). Intensive surgical and/or nonsurgical treatment may worsen their symptoms, and sufficient treatment could not be given. However, the effect of MG on post-recurrence survival remains controversial. Fiorelli et al. reported better survival in patients without MG than in those with MG (11). Chiappetta et al. reported opposite outcomes of better OS and DFS in patients with MG (14). They commented on the potential associations between MG and early disease and the impact of intensive surveillance performed by oncological and neurological physicians. They concluded that the relationship between MG and thymoma prognosis remains unclear. Other studies have not demonstrated significant associations between MG and the outcomes of patients with recurrent thymoma and TETs (6,7,13).

Nonsurgical treatment for recurrence

Although surgical resection is recommended for resectable recurrent TETs, nonsurgical treatment is indicated for cases of unresectable recurrence owing to the extent of the disease or medical reasons. In patients without a history of chemotherapy, cisplatin-based combination regimens are indicated: a combination of cisplatin, doxorubicin, and cyclophosphamide, and cisplatin and etoposide as the primary chemotherapy for advanced disease. In patients with a history of chemotherapy, re-administration of a previously effective regimen was considered. Other second-line treatment options include carboplatin plus paclitaxel or cisplatin plus etoposide (2,25). In TC cases, immune checkpoint inhibitors (ICIs), which block the programmed cell death-1 (PD-1) pathway (PD-1 and PD-L1), have changed the treatment. Several phase II trials have shown improved objective response rates (ORRs) and median PFS after ICI monotherapy with pembrolizumab or nivolumab (26-28). Specifically, Cho et al. reported a median PFS of 6.1 months with pembrolizumab therapy in the pretreated TETs cohort. They also reported including one third of enrolled patients experienced recurrence following resection (27). Recently, a phase II trial was conducted to establish the safety and efficacy of atezolizumab in combination with carboplatin and paclitaxel (29). As for molecular targeted therapy, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-kinase inhibitor lenvatinib showed promising outcomes in patients previously treated with cisplatin. The median OS was 28.3 months, and the OS rate at 36 months was 35.7% (30).

Radiotherapy has been an option for treatment in combination with chemotherapy in cases with unresectable local or limited extent of the disease. Recent intensity-modulated radiotherapy (IMRT) techniques have shown advantages in target coverage and avoidance of normal tissue. This modality provides good local control for patients with pleural disease and can be an option for patients for whom surgery is unfeasible (31,32).

Conclusions

The recurrence of TETs after resection is a heterogeneous disease in terms of the malignant potential of the tumor itself and the mode of recurrence. In recurrent TCs and TNENs, DFIs are commonly shorter than those in thymomas, and rapid progression and extension are observed. Re-resections may be indicated for localized disease, and prolonged PRS is expected in selected TC/TNEN patients for re-resections. Conversely, thymomas rarely present with distant metastases, and recurrent diseases often develop at local and pleural sites. We frequently recommend re-resection for patients with recurrent thymoma because of these tumor characteristics.

Furthermore, the PRS of thymomas with re-resection was more favorable than that of TCs and TNENs. As potential prognostic factors, WHO histological type, stage, and DFI have been proposed, and indications for re-resection have been decided, considering the presence of those factors. However, the effect of MG on the outcomes of patients with recurrent thymomas is controversial. For locally invasive and pleural diseases, especially thymomas, a multimodal approach might be an option for complete re-resection and disease control. Although survival in patients with re-resected TETs of a less aggressive nature is favorable compared with that of nonsurgical ones, how the surgical interventions themselves prolong PRS has not yet been proven. Further exploration and debate are required regarding the efficacy of re-resection for recurrent TETs.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-26/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-26/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105:546-51. [Crossref] [PubMed]
2. Girard N, Ruffini E, Marx A, et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26:v40-55. [Crossref] [PubMed]
3. NCCN Clinical Practice Guidelines in Oncology. Thymomas and Thymic Carcinomas. Version 1. 2024. Available online: https://www.nccn.org/professionals/physician_gls/pdf/thymic.pdf
4. Bott MJ, Wang H, Travis W, et al. Management and outcomes of relapse after treatment for thymoma and thymic carcinoma. Ann Thorac Surg 2011;92:1984-91; discussion 1991-2. [Crossref] [PubMed]
5. Hamaji M, Allen MS, Cassivi SD, et al. The role of surgical management in recurrent thymic tumors. Ann Thorac Surg 2012;94:247-54; discussion 254. [Crossref] [PubMed]
6. Mizuno T, Okumura M, Asamura H, et al. Surgical management of recurrent thymic epithelial tumors: a retrospective analysis based on the Japanese nationwide database. J Thorac Oncol 2015;10:199-205. [Crossref] [PubMed]
7. Margaritora S, Cesario A, Cusumano G, et al. Single-centre 40-year results of redo operation for recurrent thymomas. Eur J Cardiothorac Surg 2011;40:894-900. [Crossref] [PubMed]
8. Yano M, Sasaki H, Moriyama S, et al. Number of recurrent lesions is a prognostic factor in recurrent thymoma. Interact Cardiovasc Thorac Surg 2011;13:21-4. [Crossref] [PubMed]
9. Bae MK, Byun CS, Lee CY, et al. Clinical outcomes and prognosis of recurrent thymoma management. J Thorac Oncol 2012;7:1304-14. [Crossref] [PubMed]
10. Marulli G, Margaritora S, Lucchi M, et al. Surgical treatment of recurrent thymoma: is it worthwhile? Eur J Cardiothorac Surg 2016;49:327-32. [Crossref] [PubMed]
11. Fiorelli A, D'Andrilli A, Vanni C, et al. Iterative Surgical Treatment for Repeated Recurrences After Complete Resection of Thymic Tumors. Ann Thorac Surg 2017;103:422-31. [Crossref] [PubMed]
12. Miyata R, Hamaji M, Omasa M, et al. The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study. Surg Today 2021;51:502-10. [Crossref] [PubMed]
13. Sandri A, Cusumano G, Lococo F, et al. Long-term results after treatment for recurrent thymoma: a multicenter analysis. J Thorac Oncol 2014;9:1796-804. [Crossref] [PubMed]
14. Chiappetta M, Zanfrini E, Giraldi L, et al. Prognostic factors after treatment for iterative thymoma recurrences: A multicentric experience. Lung Cancer 2019;138:27-34. [Crossref] [PubMed]
15. Chiappetta M, Lococo F, Zanfrini E, et al. The International Thymic Malignancy Interest Group Classification of Thymoma Recurrence: Survival Analysis and Perspectives. J Thorac Oncol 2021;16:1936-45. [Crossref] [PubMed]
16. WHO Classification of Tumours Editorial Board. Thoracic tumours. WHO classification of tumours. 5th ed 5. Lyon, France: International Agency for Research on Cancer; 2021.
17. Detterbeck FC, Asamura H, Crowley J, et al. The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies. J Thorac Oncol 2013;8:1467-73. [Crossref] [PubMed]
18. Ruffini E, Detterbeck F, Van Raemdonck D, et al. Thymic carcinoma: a cohort study of patients from the European society of thoracic surgeons database. J Thorac Oncol 2014;9:541-8. [Crossref] [PubMed]
19. Hishida T, Nomura S, Yano M, et al. Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study. Eur J Cardiothorac Surg 2016;49:835-41. [Crossref] [PubMed]
20. Huang J, Rizk NP, Travis WD, et al. Comparison of patterns of relapse in thymic carcinoma and thymoma. J Thorac Cardiovasc Surg 2009;138:26-31. [Crossref] [PubMed]
21. Choe G, Ghanie A, Riely G, et al. Long-term, disease-specific outcomes of thymic malignancies presenting with de novo pleural metastasis. J Thorac Cardiovasc Surg 2020;159:705-714.e1. [Crossref] [PubMed]
22. Aprile V, Bacchin D, Korasidis S, et al. Surgical treatment of pleural recurrence of thymoma: is hyperthermic intrathoracic chemotherapy worthwhile? Interact Cardiovasc Thorac Surg 2020;30:765-72. [Crossref] [PubMed]
23. Ishikawa Y, Matsuguma H, Nakahara R, et al. Multimodality therapy for patients with invasive thymoma disseminated into the pleural cavity: the potential role of extrapleural pneumonectomy. Ann Thorac Surg 2009;88:952-7. [Crossref] [PubMed]
24. Nakamura S, Kawaguchi K, Fukui T, et al. Multimodality therapy for thymoma patients with pleural dissemination. Gen Thorac Cardiovasc Surg 2019;67:524-9. [Crossref] [PubMed]
25. Lemma GL, Lee JW, Aisner SC, et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma. J Clin Oncol 2011;29:2060-5. [Crossref] [PubMed]
26. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-55. [Crossref] [PubMed]
27. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019;37:2162-70. [Crossref] [PubMed]
28. Katsuya Y, Horinouchi H, Seto T, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer 2019;113:78-86. [Crossref] [PubMed]
29. Asao T, Shukuya T, Mimori T, et al. Study Design and Rationale for Marble Study: A Phase II Trial of Atezolizumab (MPDL3280A) Plus Carboplatin and Paclitaxel in Patients With Advanced or Recurrent Thymic Carcinoma (JTD2101). Clin Lung Cancer 2023;24:e247-53. [Crossref] [PubMed]
30. Niho S, Sato J, Satouchi M, et al. Long-term follow-up and exploratory analysis of lenvatinib in patients with metastatic or recurrent thymic carcinoma: Results from the multicenter, phase 2 REMORA trial. Lung Cancer 2024;191:107557. [Crossref] [PubMed]
31. Basse C, Thureau S, Bota S, et al. Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort. J Thorac Oncol 2017;12:1715-22. [Crossref] [PubMed]
32. Wang CL, Gao LT, Lyu CX, et al. Intensity Modulated Radiation Therapy for Pleural Recurrence of Thymoma: A Prospective Phase 2 Study. Int J Radiat Oncol Biol Phys 2021;109:775-82. [Crossref] [PubMed]